**Conflict of interest**

internalized Ags into pieces with epitopes, which are finally bound to MHC-II (major histocompatibility complex II) and/or MHC-I and displayed on cell surfaces for presentation to T cells [29]. MHC-I molecules are assembled in the endoplasmic reticulum (ER) with stabilization by chaperone proteins (including calreticulin, Erp57, protein disulfide isomerase (PDI), and tapasin) and are loaded, under tapasin mediation, with exogenous (viral or self-originated) Ags, which are translocated from the cytoplasm into the ER by TAP (transporter associ-

their activation [30]. MHC-II molecules are assembled in the ER, stabilized by an invariant chain (Ii) and transported through the Golgi to fuse with a late endosome forming the MHC-II endosome compartment (MIIC) with an acidic interior containing proteases cathepsin S and cathepsin L, which when activated will digest Ii, leaving in the peptide-binding groove of the MHC-II a residual class II-associated Ii peptide (CLiP), which later is exchanged for an antigenic peptide (usually exogenous Ags) derived from a protein degraded in the endosomal

During Ag presentation, a substantial number of various signaling cytokines such as interleukins and interferons, as well as chemokines, are secreted by matured APCs and other

either T-helper type-1 (Th1) cells that will secrete IFN-γ, IL-12, and IL-2 or Th2 cells that will secrete IL-4. Then, Th1 cells will further secrete IL-12 and IFN-γ facilitating the MHC-I-Ag

T lymphocytes (CTLs), thus establishing the cellular immunity while forming memory T cells [31, 32]. Meanwhile, the Th2 cells mature to favor Ag presentation to B cells via B cell receptors (BCRs) and to secrete IL-4, IL-6, and IL-10, which are also beneficial for promoting the Ag-activated B cells to proliferate and differentiate into plasma cells to produce the anti-Ag antibodies, establishing finally the humoral immunity while forming memory B cells [33]. With memory T and B cells, upon encountering pathogens, both humoral and cellular immunity can be rapidly established; while humoral immunity neutralizes the extracellular pathogens during or before the infection and thus is fitting for the prophylaxis of pathogen invasion, cellular immunity is mainly responsible for destroying already infected or abnormal human cells and therefore may be employed for the clearance of the cell-hidden pathogens or malignant tumors, through specialized TCR recognition of the precisely matched Ags nestled

**3. Immunization: vaccine adjuvant-delivery system and strategies**

In designing the NP-based VADSs, what should be emphasized is that the differently sourced Ags are processed and trigger immune signal transduction in different ways [34]. Usually, the internalized exogenous Ags delivered by NPs are processed intracellularly by APCs into small antigens just inside the endolysosomal vesicles and then loaded favorably on MHC-II molecules, leading to activation of CD4+ T cells to differentiate into Th2 cells, which will further stimulate production of antibodies by B cells [8]. In contrast, the endogenous Ags, such as viral Ags, cancer components, and intracellular-degraded proteins, are usually presented in the cytosol and often

T cells to proliferate and differentiate into the Ag-specific cytotoxic

T cells for

T cells for their activation [30].

T-cell differentiation into

ated with antigen presentation) for presentation via T-cell receptors (TCRs) to CD8<sup>+</sup>

pathway for presentation via T-cell receptors (TCRs) to CD4<sup>+</sup>

4 Immunization - Vaccine Adjuvant Delivery System and Strategies

epitope-triggered CD8<sup>+</sup>

in the groove of MHC-I on cells [12].

immunocytes to promote the MHC-II-Ag epitope-triggered CD4<sup>+</sup>

All the authors declared no conflict of interest.
